Molecular mechanism of hematopoietic regulation by leukemia-related transcription factor AML1(PEBP2αB)

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We analyzed the molecular mechanism of actions played by leukemia-related transcription factor, AML1(PEBP2αB), on hematopoietic regulation by using an in vitro experimental system, which was newly established through this research project. Our results are summarized as follows :1. We established an in vitro experimental system by using murine embryonic stem(ES) cell differentiation, through which the in vivo hematological phenotype observed in the AML1-deficient animals could be replicated in vitro.2. The hematopoietic defect resulting from homozygous null allele for AML1 could be rescued by re-expressing wild-type AML1 cDNA, indicating compelling evidence that the AML1-knockout phenotype is due solely to the lack of this gene.3. This rescue was observed in vivo in that the rescue clones contribute to lympho-hematopoiesis in chimera mice.4. The rescue required the transactivation domain of AML1 molecule.5. Forced expression of the same AML1 cDNA did not rescue the hematopoietic defect, suggesting that transcriptional control of AML1 was important for the biologic activity of the PEBP2 transcription complex. Consistent with this observation, the expression level of AML1 fluctuated as ES cells differentiated in vitro.6. We analyzed the expression of the known AML1-target genes and found that most of them were retained even in the absence of the active AML1 molecule. Therefore, it is suggested that as yet un-identified transcriptional target(s) exists which mediates AML1's biologic activities.